Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Sohag University, Sohag, 82524, Egypt.
Int Immunopharmacol. 2023 Sep;122:110498. doi: 10.1016/j.intimp.2023.110498. Epub 2023 Jul 5.
Hepatic ischemia/reperfusion injury (IRI) is a clinical problem commonly during liver transplantation and other liver surgery. This study aimed to evaluate the protective effect of zafirlukast (ZFK) on IR-induced hepatic injury and investigate its relevant protective mechanism. Thirty-two male Wistar albino rats were randomly allocated to four groups: sham, IRI, ZFK, and ZFK + IR groups. ZFK was administered orally in a dose of 80 mg/kg/day for 10 consecutive days. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBL) levels, and gamma glutamyl transferase (GGT) activity were estimated. Liver tissues were used to assess oxidative stress biomarkers including malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NOx), and reduced glutathione (GSH) contents. Inflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-33 (IL-33), in addition to apoptosis biomarkers, BCL2 associated X protein (Bax), B-cell lymphoma 2 (Bcl2) and galactine-9 (GAL9) proteins were also assessed. Western blot analysis was performed for vascular endothelial growth factor (VEGF) and fibrinogen expressions. Immunohistochemical analysis for hepatic nuclear factor-kappa B (NF-κB) and SMAD-4 was done in addition to histopathological examination. Our study revealed that ZFK pre-treatment resulted in liver function restoration and oxidative stress correction. Moreover, inflammatory cytokines were significantly reduced and a remarkable reduction of apoptosis, angiogenesis, and clotting formation has been indicated. Additionally, a significant reduction in SMAD-4 and NF-kB protein expressions was observed. These results were supported by hepatic architecture improvement. Our findings revealed that ZFK possesses a potential protective effect against liver IR possibly through its antioxidant, anti-inflammatory and anti-apoptotic properties.
肝缺血再灌注损伤（IRI）是肝移植和其他肝手术中常见的临床问题。本研究旨在评估扎夫鲁司特（ZFK）对 IR 诱导的肝损伤的保护作用，并探讨其相关的保护机制。32 只雄性 Wistar 白化大鼠随机分为四组：假手术组、IRI 组、ZFK 组和 ZFK+IRI 组。ZFK 以 80mg/kg/天的剂量口服给药，连续 10 天。测定血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、总胆红素（TBL）水平和γ-谷氨酰转移酶（GGT）活性。用肝组织评估氧化应激生物标志物，包括丙二醛（MDA）、髓过氧化物酶（MPO）、一氧化氮（NOx）和还原型谷胱甘肽（GSH）含量。还评估了炎症细胞因子肿瘤坏死因子-α（TNF-α）和白细胞介素-33（IL-33）以及凋亡生物标志物 B 细胞淋巴瘤 2 相关 X 蛋白（Bax）、B 细胞淋巴瘤 2（Bcl2）和半乳糖-9（GAL9）蛋白。还进行了血管内皮生长因子（VEGF）和纤维蛋白原表达的 Western blot 分析。此外，还进行了肝核因子-κB（NF-κB）和 SMAD-4 的免疫组织化学分析以及组织病理学检查。我们的研究表明，ZFK 预处理可恢复肝功能并纠正氧化应激。此外，炎症细胞因子显著减少，凋亡、血管生成和凝血形成明显减少。此外，SMAD-4 和 NF-κB 蛋白表达也显著减少。这些结果得到了肝结构改善的支持。我们的研究结果表明，ZFK 具有潜在的保护作用，可能通过其抗氧化、抗炎和抗凋亡特性。
